Modulating Cortical and Sub-cortical Brain Circuits in Chronic Facial Pain Chronic pain, especially facial pain is difficult to treat because it is associated with an enormous diversity of nervous system alterations. Characterizations of these changes at the molecular level, using animal models, have yielded insights that largely have not translated to the human, perhaps because the molecular complexity of the changes insures that significant differences will exist when comparing across species. At a neural circuit level, on the other hand, it may be possible to define endophenotypes that correlate with pain state, that may better generalize across species (and across patients) because they are convergently downstream of many different upstream molecular changes, and may causally be associatable with, or predict, pain state. Accordingly, we propose to study rat models of pain by optically silencing, in a temporally-precise manner, candidate brain regions in the pain circuit using novel methods we have developed, and assessing the impact on pain behavior, as well as on the pain circuit using functional magnetic resonance imaging (fMRI). In this way we will parse out the brainwide contribution of a neural circuit to pain endophenotype. By expanding our investigation beyond pain behaviors we will better understand the global behavioral effects of chronic pain and the role(s) of specific CNS regions in modulating these behavioral effects, and hopefully better model chronic pain in humans. PUBLIC HEALTH RELEVANCE: Determining the neural substrates that define the chronic facial pain state is a key step in developing treatments that generalize from basic research to humans, and also that generalize across human patients. By moving beyond the combinatorial complexity of molecular changes, to the understanding of how pain is represented in the brain, as described by optical neural control and functional brain imaging, we will develop new biomarkers for pain that accurately reflect the pain state, thus advancing the state of therapy, diagnosis, and drug discovery.